Accumulating evidence, including a wide distribution of specific receptors for aldosterone in the brain, has revealed a potential role of aldosterone in the central nervous system. However, whether or not aldosterone is present in cerebrospinal fluid remains unclear. We attempted to detect aldosterone in cerebrospinal fluid in 14 normotensive subjects. Cerebrospinal fluid was obtained by lumbar puncture. Aldosterone-like immunoreactivity was detected in cerebrospinal fluid (163±5 pmol/l, range 139-211 pmol/l) and was found to significantly correlate to both plasma aldosterone (r = 0.70, p<0.01) and plasma renin activity (r=0.68, p<0.01). However, no significant relationship was found between aldosterone-like immunoreactivity in cerebrospinal fluid and the level of sodium or potassium in cerebrospinal fluid or mean blood pressure. Although we confirmed the presence of aldosterone-like immunoreactivity in cerebrospinal fluid of normotensive subjects, the physiological role of aldosterone in cerebrospinal fluid has yet to be elucidated. Further study will thus be needed to determine the role of cerebrospinal fluid aldosterone.
Yo Kageyama, Hiromichi Suzuki and Takao Saruta
Hiromichi Suzuki, Kazuoki Kondo and Takao Saruta
The present study was performed to assess the influence of potassium on blood pressure in deoxycorticosterone (DOCA) salt hypertensive rats. The effects of potassium administration on the systolic blood pressure, fluid intake, urine volume, excretion of sodium and potassium, serum sodium and potassium, plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were investigated both during the first 2 weeks of development of DOCA salt hypertension and during the next 2 weeks of established DOCA salt hypertension. Potassium administration prevented the development of DOCA salt hypertension and reduced the blood pressure in established DOCA salt hypertension. Fluid intake, urine volume, and excretion of sodium and potassium appeared to be markedly increased in rats treated with potassium. The levels of serum sodium and potassium were unchanged by potassium loading. Both the PRA and PAC which were suppressed in DOCA salt hypertensive rats, were reversed in rats treated by potassium loading. It is suggested that the elevation of blood pressure may be prevented and the increased blood pressure reduced mainly by the diuresis and natriuresis caused by potassium loading.
Yo Kageyama, Hiromichi Suzuki and Takao Saruta
Changes in plasma aldosterone, plasma renin activity, plasma cortisol, serum sodium and potassium concentrations were studied in 9 patients with thromboembolic diseases treated with heparin. Heparin was administered at doses of 700-1000 units/h for 7-10 days. Plasma aldosterone decreased from 239±33 to 114±25 pmol/l during heparin therapy and returned to basal levels after discontinuation of the therapy. In addition, responses to a low sodium intake (3 g/day) and ACTH were examined in 5 patients during and 2 weeks after heparin therapy. The increase in plasma aldosterone caused by low sodium intake was significantly attenuated during heparin therapy (124±5% increase from baseline) as compared with that 2 weeks after heparin therapy (148±7%, p<0.05). On the other hand, ACTH stimulated plasma aldosterone similarly during and at 2 weeks after heparin therapy (increase from baseline: 190±20% vs 193±9%). These results suggest that heparin decreased plasma aldosterone owing to attenuation of the angiotensin Il-induced aldosterone production.
Toyohisa Eguchi, Ikuo Saito, Ryuichi Nakamura, Toshiyuki Yasui and Takao Saruta
To study effects of angiotensin I converting enzyme inhibitor (CEI), SQ 14225, on plasma aldosterone (PA), angiotensin I (AI), angiotensin II (AII), potassium and ACTH were administered with or without the simultaneous injection of SQ 14225 in rabbits. The direct effect of bradykinin on PA was also examined, since it is suspected to augment the action of kinin under the administration of CEI.
In rabbits the dose of 1 mg/kg of SQ 14225 by a bolus injection resulted in a marked elevation of plasma renin activity (PRA) and moderate but significant decreases in circulating AII and PA with only a little change of blood pressure. Decrements in circulating AII and those in PA observed after the injection of SQ 14225 were well correlated (r = 0.585, P < 0.05). Stimulatory effects of AII, potassium and ACTH on PA were not affected by SQ 14225, however, those of AI on PA and blood pressure were completely inhibited by pre-treatment of SQ 14225. The infusion of bradykinin showed a remarkable reduction in blood pressure and a small increment in PRA, circulating AII and PA.
These results may suggest that the inhibitory effect of acutely administered SQ 14225 on PA is mainly due to the inhibition of conversion from AI to AII, but not direct effects on adrenal glands. Furthermore, it was suggested that the augmented kinin is not related to the inhibitory effect of SQ 14225 on PA. In addition, the administration of SQ 14225 does not change the effects of potassium and ACTH on PA.
Tadashi Yoshida, Matsuhiko Hayashi, Toshiaki Monkawa and Takao Saruta
Yoshida T, Hayashi M, Monkawa T, Saruta T. Regulation of obese mRNA expression by hormonal factors in primary cultures of rat adipocytes. Eur J Endocrinol 1996;135:619–25. ISSN 0804–4643
The obese (ob) gene has been cloned recently and its protein product is called "leptin". Leptin is an adipocyte-derived satiety factor that regulates body weight homeostasis. Several hormonal factors have been reported to regulate ob mRNA expression. To determine which factors are most important for regulation of ob mRNA expression, we examined the effects of insulin, dexamethasone, a β3-adrenergic agonist (CGP12177A), 8-bromo-cAMP, 8-bromo-cGMP and 1-methyl-3-isobutylxanthine (MIX) on primary cultured adipocytes. Rat adipocytes obtained from epididymal fat were cultured using the ceiling method. Total RNA was extracted and the expression of ob mRNA was measured by quantitative reverse transcription-polymerase chain reaction. After 24 h of incubation, 100 nmol/l insulin significantly increased the expression of ob mRNA (21.4-fold compared to control). Moreover, insulin increased ob mRNA expression in a dose-dependent manner over a range of 1–100 nmol/l. The effect of 100 nmol/l insulin was similar to that seen with 20% newborn calf serum. Dexamethasone (25–1000 nmol/l) also increased ob mRNA expression (2.5–2.9-fold). The effect of dexamethasone occurred more rapidly than insulin. CGP12177A (1–10 μmol/l) and 0.5 mmol/l 8-bromo-cAMP had no effects, whereas 0.5 mmol/l 8-bromo-cGMP and 0.5 mmol/l MIX had stimulatory effects (2.8- and 2.4-fold increase in ob mRNA, respectively). The combination of 250 nmol/l dexamethasone and 0.5 mmol/l MIX did not have an additive effect on ob mRNA levels. Our present data suggest that, of these agents, insulin is the most important factor regulating ob mRNA expression.
Matsuhiko Hayashi, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160, Japan
Sadao Nakajima, Hiromichi Suzuki, Ikuo Saito and Takao Saruta
Abstract. This study was undertaken to examine the effects of atrial natriuretic peptide (ANP), dopamine, and ouabain, which each are considered to be a kind of natriuretic factor, on aldosterone synthesis in vivo and in vitro. In the in vivo experiments, during infusion of one of the natriuretic factors, ANP (64 pmol · min−1 · kg−1), dopamine (20 nmol · min−1 · kg−1) or ouabain (684 pmol · min−1 · kg−1), the stimulatory action of angiotensin II (20 pmol · min−1 · kg−1) or adrenocorticotropin (ACTH, 7 pmol · min−1 · kg−1) on aldosterone synthesis was investigated in 36 anaesthetized (pentobarbital, 40 mg/kg, iv) female rabbits. In the basal condition, aldosterone synthesis was suppressed slightly by each of the natriuretic factors. The stimulatory actions of angiotensin II and ACTH on aldosterone synthesis were significantly attenuated by pre-treatment with ANP and dopamine. However, ouabain infusion did not induce any changes in the synthesis of aldosterone, 18-hydroxycorticosterone (18-OHB), and corticosterone (B) in either the basal or the stimulated conditions. For the in vitro experiments, rabbit adrenal glomerulosa cells (105 cells/tube) were used. The effects of ANP and dopamine on the aldosterone synthesis revealed results identical to those from the in vivo study. However, in contrast to the in vivo study, ouabain completely inhibited the synthesis of aldosterone, 18-OHB and B. The above results obtained in vivo and in vitro suggest that ANP inhibits corticosterone methyloxidase II activity and dopamine inhibits corticosterone methyloxidase I activity. However, from the present study we were unable to specify the action of ouabain on the synthesis of aldosterone and its related substances.
Masaki Fujimaki, Shusaku Nagahama, Hiroko Suzuki, Ikuo Saito and Takao Saruta
Abstract. To study the effect of hypokalaemia in the regulation of aldosterone secretion, repeated injections of frusemide (3 mg/kg) plus saline with or without simultaneous infusion of potassium chloride (1 mEq/kg/h) were performed in 24 conscious female rabbits for 7 h. Without potassium supplementation, the plasma renin activity (PRA) remained elevated throughout the study, while an initial increase (1 h to 3 h) in plasma aldosterone (PA) gradually returned to normal with reduction of the serum potassium. In rabbits on potassium supplements to prevent the development of hypokalaemia, both PRA and PA remained elevated. The incremental aldosterone response to administration of potassium chloride, angiotensin II or ACTH, was considerably smaller in potassium-depleted rabbits than in potassium-repleted rabbits. These results suggest that serum potassium modulates the effects of angiotensin II or ACTH on aldosterone secretion, and that a certain level of potassium is necessary to maintain the aldosterone secretory capacity of the adrenal gland.
Hirotaka Shibata, Hiromichi Suzuki, Tadashi Ogishima, Yuzuru Ishimura and Takao Saruta
We examined both activities and amounts of steroidogenic cytochrome P-450s at the posttranslational protein level and steroid contents in the adrenocortical adenoma from patients with primary aldosteronism and Cushing's syndrome. Aldosterone synthase cytochrome P-450 (human P-450aldo) was detected in the tumour portion of aldosterone-producing adenoma, but not in the normal control adrenals, at the protein level. Neither the activities nor the amounts of other P-450s in the tumour portion of aldosterone-producing adenoma were significantly different from those in the non-tumour portion in the adenoma and the normal control adrenals. The aldosterone content was significantly elevated, while the androstenedione content was significantly decreased in the tumour portion of the adenoma compared with that in the normal control adrenals. In Cushing's syndrome, both the activities and amounts of P-45017α and P-450c21 were significantly elevated in the tumour portion compared with the non-tumour portion of the adenoma and the normal control adrenals, while those of P-450scc and P-45011β in the tumour portion were not significantly different from the normal control adrenals. The cortisol content was significantly elevated, while the amounts of aldosterone and 18-hydroxydeoxycorticosterone in the tumour portion of the adenoma were significantly decreased compared with those in the normal control adrenals. These results demonstrate that overexpression of P-450aldo in aldosterone-producing adenoma, and those of P-45017α and P-450c21 in cortisol-producing adenoma may play some role in the pathogenesis of primary aldosteronism and Cushing's syndrome, respectively.
Matsuhiko Hayashi, Shigetoshi Senba, Ikuo Saito, Waichi Kitajima and Takao Saruta
Abstract. To examine potassium homeostasis in diabetes mellitus, we observed the effect of dietary potassium loading on the renin-angiotensin-aldosterone system and potassium balance in streptozotocin-induced diabetic rats. In diabetic rats with 26.51 ± 1.89 mmol/l of serum glucose, the plasma renin activity (PRA), plasma aldosterone (PA), immunoreactive insulin (IRI) and urinary excretion of prostaglandin E2 (PGE2) were all significantly lower than in control rats, but the plasma potassium and renal function were not significantly different. With potassium loading, both control and diabetic rats showed a similar increase in plasma potassium and urinary potassium excretion and a decrease in PRA, but the IRI, plasma corticosterone and urinary excretion of PGE2 exhibited no significant change. On the other hand, the PA was significantly increased only in the control rats, and not in the diabetic rats on potassium loading. Based up on these results, it is suggested that potassium homeostasis is well maintained in diabetic rats with normal renal function in spite of an attenuated response of aldosterone secretion to dietary potassium loading and insulin deficiency.
Sadao Nakajima, Hiromichi Suzuki, Yo Kageyama, Takashi Takita and Takao Saruta
Abstract. The effects of atrial natriuretic peptide (ANP) on mean arterial blood pressure, heart rate, plasma renin activity, aldosterone, cortisol, norepinephrine, epinephrine and arginine vasopressin were studied in 6 anuric subjects receiving regular hemodialysis. An iv bolus injection of 8 nmol of ANP followed by infusion at 32 pmol·kg−1·min−1 for 1 h in the pre- and posthemodialysis period was performed. Basal plasma ANP was higher before than after hemodialysis. ANP administration produced a reduction in mean arterial blood pressure accompanied by an elevation of norepinephrine and of plasma renin activity (from 2.49 ± 0.52 to 3.39 ± 0.85 nmol·l−1·h−1 predialysis and from 2.78 ± 0.71 to 3.15 ± 0.86 nmol·l−1·h−1 postdialysis, respectively, mean ± sem; P < 0.05). Plasma aldosterone and cortisol were significantly decreased. Plasma epinephrine and AVP remained unchanged. These hemodynamic and hormonal changes were similar in the pre- and the postdialysis period. These results suggest that 1) ANP causes a fall in mean arterial blood pressure, which in turn induces reflex tachycardia and activation of the sympathetic nervous system without diuresis; 2) the activated sympathetic nervous system as reflected in elevation of plasma norepinephrine may increase plasma renin activity; 3) reduced plasma aldosterone is not influenced by enhancement of the reninangiotensin system; therefore, 4) reduction of plasma aldosterone as well as cortisol is probably due to direct action of ANP, and finally 5) AVP had no direct relation with ANP administration.